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Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with irinotecan: results of an open-label, phase 1 study

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Abstract

Purpose

The oral Bcl-2 inhibitor navitoclax demonstrated activity in solid and hematologic malignancies as monotherapy and in combination with other cytotoxic agents in preclinical and early clinical studies. We evaluated the safety, pharmacokinetics (PK), and antitumor activity of navitoclax plus irinotecan.

Methods

In this multicenter, open-label, phase 1 dose escalation study, adults with advanced solid tumors received navitoclax (starting dose 150 mg/day) in combination with 1 of 2 irinotecan schedules during a 21-day cycle: a once-every-3-week regimen (Q3W 180, 250, or 350 mg/m2) or a once-weekly regimen (QW 75 or 100 mg/m2). Enrollment occurred until a maximum tolerated dose (MTD) and/or recommended phase 2 dose (RPTD) was reached.

Results

All patients (Q3W, n = 14; QW, n = 17) were evaluable for safety, PK, and efficacy. The most common adverse event in both groups was diarrhea (Q3W 92.9 %; QW 76.5 %), which was the most frequent grade 3/grade 4 adverse event (Q3W 42.9 %; QW 29.4 %). The study was amended to exclude 4 UGT1A1*28 7/7 homozygous patients due to frequent irinotecan-related grade 3/grade 4 diarrhea and/or febrile neutropenia. No apparent PK interactions between navitoclax and irinotecan were observed. The MTD of the combination was exceeded in the Q3W group at the lowest dose administered. In the QW group, the MTD and RPTD for navitoclax were 150 mg when combined with irinotecan 75 mg/m2. One patient in each group achieved a partial response.

Conclusion

The RPTD of navitoclax in combination with irinotecan 75 mg/m2 QW during a 21-day cycle was 150 mg in these heavily pretreated patients.

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Acknowledgments

We acknowledge the patients and their caregivers for their participation in this study. We also acknowledge Kenneth Idler, who performed the UGT1A1 assays, and medical writing assistance from Yvonne E. Yarker, PhD, which was supported by AbbVie Inc. AbbVie Inc. and Genentech funded the studies.

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Authors and Affiliations

  1. South Texas Accelerated Research Therapeutics (START), 4383 Medical Dr., San Antonio, TX, 78229, USA

    Anthony W. Tolcher

  2. Yale Cancer Center, Yale University, New Haven, CT, USA

    Patricia LoRusso

  3. AbbVie Inc., North Chicago, IL, USA

    Jennifer Arzt, Todd A. Busman, Guinan Lian, Niki S. Rudersdorf, Carol Ann Vanderwal, Jeffrey F. Waring, Jianning Yang & Kyle D. Holen

  4. UCLA Division of Hematology-Oncology, Santa Monica, CA, USA

    Lee S. Rosen

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  1. Anthony W. Tolcher
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Corresponding author

Correspondence to Anthony W. Tolcher.

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Conflict of interest

Anthony W. Tolcher has advisory/consulting agreements with AbbVie, Akebia, AP Pharma, ArQule, Inc., Asana, Astex, Avid Biologics, Bayer HealthCare, Bind Therapeutics, BioMed Valley Discoveries, Blend Therapeutics, Bristol-Myers Squibb Japan, Celator, Clovis, Curis, De Novo Sciences, Dicerna, Eisai, Endo, Genentech, Heron, Janssen, Lilly MedImmune, Mersana, Merus, Nanobiotix S.A., Nektar, Neumedicines, Novartis, Pfizer, Pharmacyclics, Pierre Fabre, Proimagen, Sanofi-Aventis, Symphogen, Vaccinex, Valent Technologies, and Zyngenia. Patricia LoRusso has no conflicts to disclose. Jianning Yang is a former employee of and owns stock in AbbVie Inc. Lee S. Rosen receives research funding from Abbott/AbbVie Inc. Jennifer Arzt, Todd A. Busman, Guinan Lian, Niki S. Rudersdorf, Carol Ann Vanderwal, Jeffrey F. Waring, and Kyle D. Holen are employees of and may own stock in AbbVie Inc.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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Tolcher, A.W., LoRusso, P., Arzt, J. et al. Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with irinotecan: results of an open-label, phase 1 study. Cancer Chemother Pharmacol 76, 1041–1049 (2015). https://doi.org/10.1007/s00280-015-2882-9

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  • DOI: https://doi.org/10.1007/s00280-015-2882-9

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